1. Field of the Invention
The present invention relates to the use of the amino acid glutamine in combination with additional nutrients in a composition for promoting recovery in patients undergoing elective surgery and for treating multiple organ system failure.
2. Description of the Related Art
Schneider et al., U.S. Pat. No. 5,902,829, discloses a method for the amelioration of microcirculatory hypoperfusion, and/or the treatment or prophylaxis or hypoperfusion-reperfusion injury, in patients in need of such amelioration, treatment or prophylaxis, comprising administering preoperatively to a patient undergoing surgery to the patient a composition comprising an effective amount of a nitric oxide donor and/or a substrate of nitric oxide synthetase and/or a precursor of the substrate, for the amelioration, treatment or prophylaxis, and a nutritionally acceptable carrier. Schneider et al. further discloses that the precursor of L-arginine is ornithine or glutamine and that the composition is administered at least one day prior to surgery, but can be initiated between 3-10 days prior to surgery.
Vinnars et al., U.S. Pat. No. 5,646,187, discloses a composition for the treatment of critically ill patients having one or more organ failures or sepsis and a general catabolism which have more than a 50% reduction of the glutamine level in skeletal muscles and under intensive care, in order to improve protein synthesis capacity, maintaining energy level, preserving the lean body mass, wherein the composition consists essentially of a conventional amino acid mixture and more than 25 gl of alpha-ketoglutarate or admixtures of these with at least one member selected from the group consisting of glutamine, L-asparagine, acetoacetate, glucose and fat.
Wilmore, U.S. Pat. No. 5,292,722, discloses a composition for decreasing dehydration and nitrogen loss in a mammal comprising from about 4% to 10% dextrose and from about xc2xd% to 2% glutamine, or glutamine equivalent, wherein said glutamine equivalent is capable of being converted to glutamine by said mammal. Wilmore discloses that the composition can be used in treating dehydration and nitrogen loss which is associated with surgical operations.
3. Discussion of the Background of the Invention
Throughout the world, multiple organ system failure (MOSF) has become the most common cause of death in intensive care units (ICU); the reported mortality rates vary from 30-100% with a mean of 50%, depending on the number of organ systems involved, the patients"" ICU stay may last for 6 weeks to many months. As used herein, the term xe2x80x9cMOSF or Multiple Organ System Failurexe2x80x9d refers to the clinical syndrome of vital organ dysfunction or failure due to tissue injury resulting from SIRS (Systemic Inflammatory Response Syndrome which refers to the excessive and dysfunctional elaboration by a human patient of inflammatory mediators which results in an excessive and injurious inflammatory response). In prior studies, patients with multiple system failure have used nearly 40% of the available ICU days. See, e.g., Carrico et al. Arch. Surg. Vol. 121 page 196(1986). For the last ten years, efforts to improve outcome based upon increasing systemic oxygen delivery have been advocated, but either no effect or increased mortality has been associated with this approach.
Gastric intramucosal pH monitoring has been advocated as a more sensitive endpoint of resuscitation and two clinical studies have suggested improved outcome in selected subsets of patients. See Gutierrez et al., Lancet, vol. 339 page 195 (1992) and Ivatury et al., J. Trauma vol. 39, page 1, (1995). Others have confirmed that failure of splanchnic resuscitation correlates with MOSF and increased length of ICU stay in a hemodynamically unstable trauma patient. See, e.g., Kirton et al., Chest, vol. 108, No. 3, page 104S (1995).
Kirton et al. have studied ICU patients with persistent uncorrected gastric intramucosal pH and who had pulmonary artery catheters to guide resuscitation. See Kirton et al., J. Trauma vol. 39, No. 6, page 1211(1995). Kirton et al. have found that the relative risk of death in patients with a pHi of less than 7.32 was 4.5 whereas the relative risk of developing multiple organ system failure was 5.4 in patients having a pHi of greater than 7.32. During the study a resuscitation protocol was begun upon ICU admission, which utilized inotropic and vasodilatory agents to optimize systemic and splanchnic O2 delivery (e.g., dubutamine, isoproterenol, prostaglandin E, nitroglycerin, nitroprusside). The xanthine oxidase inhibitor, folate, and the free radical scavenger, mannitol, were uniformly administered. Drugs causing splanchnic vasoconstriction (e.g., epinephrine, norephinephrine, meosynephrine) were only used to treat severe systemic hypotension. This protocol resulted in a significant reduction in multiple organ system failures per patient and length of ICU and total hospital stay in patients with persistent gastric intramucosal acidosis. The agents administered increased splanchnic perfusion and were intended to prevent free radical damage during reperfusion. The study concluded that the severity of MOSF as judged by defined organ system failures and duration of stay were associated with gastrointestinal intramucosal acidosis related to splanchnic hypoperfusion. However, the problem of reversing the abnormal pHi and curtailing the long ICU stay indicated that further improvements are necessary.
Multiple organ system failure is associated with ischemia-reperfusion injury. Oxygen radicals are involved during ischemia followed by reperfusion. Therapy to block xanthine oxidase and thus prevent the generation of free radicals (e.g., superoxicde:O2, hydrogen peroxide:H2O2, and the hydroxyl radical:OH) and promote the generation of radical scavengers to prevent damage when radicals have already been generated are essential to treatment of multiple organ system failure. The oxygen free radicals are capable of causing cellular injury through cellular membrane lipid peroxidation and degradation of nucleic acids, eventually leading to increased membrane permeability and cell-lysis. Certain free radical species, including O2xe2x80x94and OH cause polymorphonuclear cells (PMNs) to be attracted to the gastrointestinal tract, adhere, and then be activated. The free radicals are then released and spread systemically, attacking normal tissue through their respiratory burst and causing further tissue injury by releasing intracellular proteases and lipases capable of autodigestion of cellular components. Free radicals also produce arachiodonic acid, leukotrienes, thromboxanes and prostaglandins through lipid peroxidation. The body""s natural antioxidant defenses to these free radicals consist principally of glutathione peroxidase, catalase and superoxide dismutase.
Some of the reactions are well known and available agents can be used in combination to either prevent their occurrence or to minimize the adverse affects of the agents produced. The first two abnormalities that occur in the period of ischemia are related to ATP regeneration and xanthine dehydrogenase function.
During normoxia ATP liberates energy for cellular work; in the presence of oxygen, however, ADP combines with hydrogen ion and ATP is re-synthesized. Hypoxanthine combines with NAD+, a reaction catalyzed by xanthine dehydrogenase, to produce xanthine and NADH.
During ischemia, however, ATP degrades beyond ADP to AMP, adenosine, inosine and finally to hypoxanthine. Xanthine dehydrogenase is converted to xanthine oxidase.
During reperfusion which reintroduces oxygen, xanthine oxidase catalyzes the transformation of hypoxanthine to xanthine which also results in the production of superoxide and hydrogen peroxide.
Later reactions produce the hydroxyl radical, superoxide, and hydrogen peroxide which create tissue injury through lipid peroxidation, destruction of protein such as ATPase, destruction of nucleic acids and membrane permeability.
Superoxide, through the process of lipid peroxidation, liberates free fatty acids, particularly arachidonic acid. Arachidonic acid is a substrate for the production of leukotrienes and prostaglandins. Superoxide in the gut also attracts, causes adherence and activation of polymorphonuclear white cells. The hydroxyl radical can also activate PMNS which subsequently liberate proteases and superoxide, the so called respiratory burst, which in the absence of a normal traditional enemy such as bacteria, results in direct tissue injuries, particularly in the pulmonary capillaries. Hydrogen peroxide also combines with superoxide to produce hydroxyl radicals in iron catalyzed reactions such as the Fenton and Haber-Weiss reactions. Thus, free radical production perpetuates further free radical production which leads to a cycle of increasing tissue injury.
PLA2, phospholipase A2, was originally thought only to be important in the process of digestion. However, it has been shown to hydrolyze cell membranes and release free fatty acids which lead to the production of prostaglandins, leukotrienes and lipoxins. It is also involved in generation of highly toxic compounds such as lysophosphatides. Finally, it has been shown to activate PAF which then attracts PMNS to the gut for activation.
During ischemia, intracellular calcium accumulates and has been associated with increasing free radical damage, activiating PLA2, increasing xanthine oxidase activity and decreasing ATP binding. All of these functions accentuate and reinforce the previously mentioned pathways of inducing tissue injury.
Glutamine has been implicated as sustaining mucosal architecture and function, thus preventing gut injury. In addition, glutamine combines with acetyl cysteine to form glutathione. In a reaction catalyzed by the selenium containing enzyme glutathione peroxidase, glutathione is transformed in order to oxidize glutathione which combines with hydrogen peroxide and degrades it to water and prevents hydrogen peroxide to react with superoxide and produce the hydroxyl radical.
To address the problems associated with free radical damage and to decrease hospital stays in patients undergoing elective surgery, the present inventors have developed a composition in unit dosage form to be administered in a therapeutic method of promoting recovery in elective surgery patients.
The present invention therefore, comprises a micronutrient composition in unit dosage form comprising L-glutamine, N-acetyl-cysteine, vitamin A, vitamin C, vitamin E, folate, magnesium, zinc, selenium and copper for use in therapeutic methods of treatment.
The present invention also relates to a method of treating a treating multiple organ system failure by administering a composition in unit dosage form comprising L-glutamine, N-acetyl-cysteine, vitamin A, vitamin C, vitamin E, folic acid, magnesium, selenium, zinc and copper.
In another embodiment, promoting recovery from an elective surgical procedure comprising administering to a patient in need thereof, prior to said elective surgical procedure and following said elective surgical procedure, as a daily regimen, a composition in unit dosage form comprising L-glutamine, N-acetyl-cysteine, vitamin A, vitamin C, vitamin E, folic acid, magnesium, selenium, zinc and copper.
In a preferred embodiment, at least two unit dosage forms of the inventive composition are administered to a patient in need thereof prior to elective surgery and following elective surgery.
In a particularly preferred embodiment, at least three unit dosage forms of the inventive composition are administered to a patient in need thereof prior to elective surgery and following elective surgery.
Additional objects, features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out in the appended claims.